Ceramides are the most abundant lipids constituting the intercellular matrix of the skin stratum corneum and their critical role in skin homeostasis has been extensively documented. Their concentration in the skin highly depends on the rate of availability of the enzymes involved in ceramide generation. The aim of this study was to investigate whether the concentration of prosaposin was altered in the skin of patients with psoriasis vulgaris. Prosaposin, the precursor of saposins (sphingolipid activator proteins), was measured in lesional and nonlesional skin of psoriatic patients and in normal skin from surgical patients, both at the mRNA and at the protein level. Densitometric analysis of reverse transcriptase-polymerase chain reaction bands separated by gel-electrophoresis showed a progressive decrease of prosaposin mRNA expression in nonlesional and lesional psoriatic skin, being substantially decreased in lesional psoriatic skin compared with normal control skin. Immunohistochemical analysis showed a significant decrease of prosaposin level in the stratum corneum of psoriatic lesional skin (both in active-type and in chronic-type plaque) compared with nonlesional and with normal skin (p < 0.01), and in psoriatic nonlesional skin compared with normal control (p < 0.05). Immunolocalization of sphingomyelinase in lesional and nonlesional psoriatic skin showed a decrease in the level of this enzyme in the stratum corneum of psoriatic lesional, compared with nonlesional skin. These results support the concept that disturbance of epidermal barrier function caused by derangement in ceramide generation can be crucial for the development of psoriatic skin diseases.